1. Field of the Invention
The present invention relates to the fields of genetics and molecular biology. More particular the invention relates to the identification of ADP-ribosylation factor-like 6 as being involved in Bardet-Biedl Syndrome (BBS), and designated here as BBS3. Defects in this gene are associated with a variety of clinical symptoms including diabetes, hypogonadism, high blood pressure, renal cancer and other defects, retinal degeneration, congenital heart defects, limb deformity or polydactyly, mental retardation and obesity. Also provided are methods of therapy and methods of screening for therapeutic compositions.
2. Description of Related Art
Bardet-Biedl syndrome (BBS [MIM 209900]) is a pleiotropic autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal abnormalities, learning disabilities, and hypogenitalism (Bardet 1920; Biedl 1922; Green et al., 1989). The disorder is also associated with an increased susceptibility to diabetes mellitus, hypertension, and congenital heart disease (Harnett et al., 1988; Green et al., 1989; Elbedour et al., 1994). The disorder shows variable expressivity within and between families, a finding suggesting genetic complexity. BBS displays extensive genetic heterogeneity and a requirement for full penetrance of two mutations at one locus and a third mutation at a second locus has been suggested (Katsanis et al., 2001). To date, eight BBS loci have been mapped, and seven BBS genes have been identified. The first three BBS genes to be discovered (BBS6, BBS2, and BBS4) are not homologous to one another and were identified using positional cloning (Katsanis et al., 2000; Slavotinek et al., 2000; Mykytyn et al., 2001; Nishimura et al., 2001). Subsequently, bioinformatics comparisons of protein sequences have aided in the identification of additional BBS genes. For example, the positional cloning of the BBS1 gene was aided by the finding of limited sequence homology to BBS2 (Mykytyn et al., 2002). BBS7 and BBS8 were identified by database searches for proteins with partial homology to BBS2 and BBS4, respectively (Ansley et al., 2003; Badano et al., 2003). BBS5 was recently identified using a combination of comparative genomics and positional cloning (Li et al., 2004).
The BBS3 locus was initially mapped to chromosome 3 in a large, inbred Israeli Bedouin kindred in a study that showed the utility of using pooled DNA samples for genetic mapping of human disorders (Sheffield et al., 1994). Genotyping of the Bedouin DNA samples initially localized the disease interval to an approximately 10 cM region. Few additional BBS3-linked families have been identified, and this has limited extensive refinement of the disease locus. However, as of yet the identity of the BBS3 gene has not been elucidated.